System and method for measuring intraocular pressure and ocular tissue biomechanical properties

ABSTRACT

Provided herein are systems and methods to measure the intraocular pressure, ocular tissue geometry and the biomechanical properties of an ocular tissue, such as an eye-globe or cornea, in one instrument. The system is an optical coherence tomography subsystem and an applanation tonometer subsystem housed as one instrument and interfaced with a computer for at least data processing and image display. The system utilizes an air-puff and a focused micro air-pulse to induce deformation and applanation and displacement in the ocular tissue. Pressure profiles of the air puff with applanation times are utilized to measure intraocular pressure. Temporal profiles of displacement and/or spatio-temporal profiles of a displacement-generated elastic wave are analyzed to calculate biomechanical properties.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation under 35 U.S.C. § 120 ofinternational patent application PCT/US2017/038799, filed Jun. 22, 2017which claims benefit of priority under 35 U.S.C. § 119(e) of provisionalapplication U.S. Ser. No. 62/353,398, filed Jun. 22, 2016, the entiretyof both of which are hereby incorporated by reference.

GOVERNMENT SUPPORT CLAUSE

This invention was made with government support under grant numbers1R01EY022362 and P30EY07551 awarded by the National Institutes ofHealth. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention generally relates to the field of eye care systemsand methods of use. More specifically, the present invention relates toa non-contact technique of measuring the intraocular pressure (IOP) andgeometry of the eye-globe with optical coherence tomography (OCT) andmeasuring biomechanical properties of ocular tissues using opticalcoherence elastography (OCE) with a single device.

Description of the Related Art

Current clinical tools provide critical information about ocular healthsuch as intraocular pressure (IOP). Noncontact applanation tonometry(NAT) is one of the most common screening tools for ocular diseases,most notably glaucoma, by measuring intraocular pressure (IOP) (1). Inaddition to IOP measurements, applanation studies have been performed totry to quantify corneal biomechanical properties for detectingdegenerative diseases such as keratoconus (2). However, the largedisplacements induced by the air-puff prohibit local assessment ofcorneal biomechanical properties (3) and cause nonlinear biomechanicalbehaviors (4). Moreover, biomechanical measurements of the cornea areconfounded by other parameters, such as IOP5,6 and central cornealthickness (CCT).5,7 Thus, providing an accurate measurement of cornealmechanical parameters (e.g., Young's modulus) is not straightforward,let alone based on applanation measurements. Nevertheless, commerciallyavailable noncontact tonometers, e.g., the ocular response analyzer andCorVis ST, can distinguish between healthy and keratoconic corneas (8),but there are conflicting results on their ability to detect cornealbiomechanical changes due to therapeutic interventions such as cornealcollagen crosslinking (8,9). Therefore, it may not be entirely possibleto separate the effects of corneal geometry, IOP, and cornealbiomechanical properties from their respective individual measurementsfor corrections.

Optical coherence tomography (OCT) is a versatile and non-invasiveimaging technique that provides depth-resolved images withmicrometer-scale resolution (10). The biomechanical properties oftissues can be measured using the elastographic functional extension ofOCT, termed optical coherence elastography (OCE) (11,12,13). While theOCT structural image has a resolution on the scale of micrometers,phase-sensitive OCT has the capability for subnanometer displacementsensitivity (14), which is crucial for ultrasensitive elastographicmeasurements (15). Ultrasound elastography and magnetic resonanceelastography are clinically available elastographic techniques, but arenot well-suited for small and thin tissues such as the cornea and thesclera, due to their relatively lower spatial resolution, poorerdisplacement sensitivities and need for contact-based excitation orcoupling medium.

Therefore, there is a recognized need for a single instrument andnoncontact imaging system that can accurately measure these parametersin a subject. Particularly the prior art is deficient in an imagingdevice, system, method, and/or technique to accurately measureintraocular pressure and biomechanical properties of ocular tissues,including corneal, retinal, or scleral tissues. The present inventionfulfills this long-standing need and desire in the art.

SUMMARY OF THE INVENTION

The present invention is directed to a system for measuring intraocularpressure, ocular tissue geometry and biomechanical properties of anocular tissue. The system comprises, in one instrument, an opticalcoherence tomography subsystem and an applanation tonometer subsystem inelectronic communication with the optical coherence tomographysubsystem. The present invention is directed to a related system thatfurther comprises a housing containing the subsystems, a computercomprising at least a memory, a processor, a digitizer, a display, andat least one network connection and an interface that is in electroniccommunication with said subsystems and with the computer.

The present invention also is directed to a method for measuringintraocular pressure, ocular tissue geometry and biomechanicalproperties in an ocular tissue in one instrument. In this method theocular tissue of an eye globe is scanned with a laser source in theoptical coherence tomography subsystem described herein and opticalcoherence tomography images are obtained. The intraocular pressure ofthe eye globe is calculated via the applanation tonometer subsystem andthe geometry of the ocular tissue is measured based on the opticalcoherence tomography images. The biomechanical properties of the oculartissue are quantified via the optical coherence tomography subsystem.The present invention is directed to a related method further comprisinga step in which one or more images obtained during the scan aredisplayed. The present invention is directed to another related methodfurther comprising a step in which one or more abnormalities in theocular tissue based on the calculated intraocular pressure, an imagedocular tissue geometry and the measured biomechanical properties isidentified.

The present invention is directed further to an applanation-opticalcoherence elastography (Appl-OCE) system for measuring intraocularpressure, an ocular geometry and biomechanical properties in an eye of asubject. The system comprises operably linked components. The systemcomponents include a scanning laser source and a scanner operably linkedto a scanner driver configured to scan the eye with radiation deliveredfrom the laser source. The system components include an air-puffgenerator configured to deliver an air-puff of a force sufficient todeform and applanate a cornea of the eye and an air-pulse generatorconfigured to deliver a focused micro air-pulse sufficient to generate alocalized displacement or an elastic wave within the eye. A computercomprises at least a memory, a processor, a digitizer, a display, and atleast one network connection and an interface in electroniccommunication with the system components. The present invention isdirected to a related applanation-optical coherence elastography(Appl-OCE) system that further comprises a housing for the components.

The present invention is directed further still to a method fordetermining the health of an eye in a subject. In the method, the eye ofthe subject is scanned with the scanning laser source and the scanner ofthe applanation-optical coherence elastography (Appl-OCE) systemdescribed herein. The air-puff and the focused micro air-pulse, asdescribed in the Appl-OCE system, are delivered to the eye. Images ofthe eye processed during the scanning and/or delivering steps aredisplayed. An intraocular pressure of the eye is measured from dataobtained after delivering the air-puff and one or more biomechanicalproperties are measured from data obtained after delivering the focusedmicro air-pulse to the eye. The intraocular pressure, ocular tissuegeometry and the one or more biomechanical properties are analyzed forpathophysiological abnormalities, thereby determining the health of theeye.

Other and further aspects, features, and advantages of the presentinvention will be apparent from the following description of thepresently preferred embodiments of the invention given for the purposeof disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

So that the matter in which the above-recited features, advantages andobjects of the invention, as well as others that will become clear, areattained and can be understood in detail, more particular descriptionsof the invention briefly summarized above may be by reference to certainembodiments thereof that are illustrated in the appended drawings. Thesedrawings form a part of the specification. It is to be noted, however,that the appended drawings illustrate preferred embodiments of theinvention and therefore are not to be considered limiting in theirscope.

FIG. 1 is a schematic of the Applanation Optical Coherence Elastography(Appl-OCE) imaging system that combines, as a subsystem, aphase-sensitive Swept Source Optical Coherence Tomography (PhS-SSOCT)system for optical coherence elastography (OCE) and an OCT-basedapplanation tonometer subsystem.

FIG. 2 depicts the temporal vertical displacement profiles of an elasticwave from the surface of a tissue-mimicking agar phantom at theindicated distances away from the excitation induced by the air-pulse.

FIG. 3 shows the comparison of the stiffness for agar phantoms atvarious concentrations (1%, 1.5%, and 2% w/w, n=3 of each concertation)assessed by optical coherence elastography and as measured by the “goldstandard” uniaxial mechanical compression testing.

FIG. 4 shows the deformation of the cornea in response to the air-puffat an artificially controlled IOP of 10 mmHg. The images are taken atthe time points of about 0 ms, 1.4 ms, 7.1 ms, 15.3 ms, and 24.5 msafter the air-puff excitation.

FIG. 5 shows the propagation of an air-pulse induced elastic wave in acorneal sample at an artificially controlled IOP of 10 mmHg. The imagesare taken at the time points of about 1.0 ms, 1.9 ms, 2.9 ms, 3.9 ms,and 4.8 ms after the air-pulse excitation.

FIG. 6 compares the intraocular pressure as measured by Appl-OCE and byrebound tonometry and includes the Young's modulus quantified by opticalcoherence elastography. The data are presented as the inter-samplemean±standard deviation of all measurements from three porcine samplesfor a given artificially controlled intraocular pressure.

DETAILED DESCRIPTION OF THE INVENTION

As used herein in the specification, “a” or “an” may mean one or more.As used herein in the claim(s), when used in conjunction with the word“comprising”, the words “a” or “an” may mean one or more than one.

As used herein “another” or “other” may mean at least a second or moreof the same or different claim element or components thereof. Similarly,the word “or” is intended to include “and” unless the context clearlyindicates otherwise. “Comprise” means “include.”

As used herein, the term “about” refers to a numeric value, including,for example, whole numbers, fractions, and percentages, whether or notexplicitly indicated. The term “about” generally refers to a range ofnumerical values (e.g., +1-5-10% of the recited value) that one ofordinary skill in the art would consider equivalent to the recited value(e.g., having the same function or result). In some instances, the term“about” may include numerical values that are rounded to the nearestsignificant figure.

In one embodiment of the present invention, there is provided a systemfor measuring intraocular pressure, ocular tissue geometry andbiomechanical properties of an ocular tissue, comprising, in oneinstrument, an optical coherence tomography subsystem; and anapplanation tonometer subsystem in electronic communication with theoptical coherence tomography subsystem. Further to this embodiment thesystem may comprise a housing containing the subsystems; a computercomprising at least a memory, a processor, a digitizer, a display, andat least one network connection; and an interface in electroniccommunication with the subsystems and with the computer. In this furtherembodiment the computer may be configured to control the subsystems, toprocess data received from the subsystems, to generate one or moreimages from processed data, and to display the one or more images. Inboth embodiments the ocular tissue may comprise an in vivo or an ex vivoeye-globe, an in vivo or an ex vivo corneal tissue, or an ocular tissuemimic.

In one aspect of both embodiments, the optical coherence tomographysubsystem may comprise means for scanning the ocular tissue, means fordelivering an air-puff to the ocular tissue and means for delivering afocused micro air-pulse to the ocular tissue. In this aspect the meansfor scanning the ocular tissue may comprise, in electroniccommunication, a scanning laser source configured to operate at about1260 nm to about 1370 nm, a resonant scanner configured to scan a laserbeam emitted by the scanning laser source across the ocular tissue and ascanner driver configured to move the resonant scanner over the oculartissue with operator-configurable scanning distance and phase. Also inthis aspect, the means for delivering the air-puff to the ocular tissuemay comprise, in combination, a rotary solenoid and a plunger configuredto deliver the air-puff with a force sufficient to deform the oculartissue. In addition, the means for delivering the air-pulse to theocular tissue may comprise, in electronic communication, an air-pulsesupply, an air-pulse controller and an electronically controlledpneumatic solenoid configured to produce the focused micro air-pulsefrom the air-pulse supply.

In another aspect of both embodiments the applanation tonometersubsystem may comprise means for delivering an air-puff to the oculartissue, means for measuring a temporal pressure profile from deformationand applanation of the ocular tissue from the air-puff delivered theretoand means for calculating an intraocular pressure from the temporalpressure profile and imaged ocular tissue deformation and applanation.In this aspect the means for measuring the temporal pressure profile ofthe ocular tissue may be a pressure transducer configured to measure anair-puff pressure at a plurality of time points during deformation andapplanation of the ocular tissue. Also the means for calculating theintraocular pressure may comprise software configured to correlate thetimes of applanation of the ocular tissue with a temporal pressureprofile and to apply corrections as needed.

In another embodiment of the present invention there is provided amethod for measuring intraocular pressure, ocular tissue geometry andbiomechanical properties of an ocular tissue in one instrument,comprising scanning the ocular tissue of an eye globe with a lasersource in the optical coherence tomography subsystem as described supra;obtaining optical coherence tomography images; calculating theintraocular pressure of the eye globe via the applanation tonometersubsystem; measuring the geometry of the ocular tissue based on theoptical coherence tomography images; and quantifying the biomechanicalproperties of the ocular tissue via the optical coherence tomographysubsystem. Further to this embodiment the method may comprise displayingone or more images obtained during the scanning step. In another furtherembodiment the method may comprise identifying one or more abnormalitiesin the ocular tissue based on the calculated intraocular pressure, animaged ocular tissue geometry and the measured biomechanical properties.In all embodiments biomechanical properties comprise axial displacement,relaxation rate, relaxation process, frequency of relaxation process,natural frequency, spectral properties, Young's modulus, elasticity,viscosity, maximum deformation, corneal thickness, corneal curvature,inward velocity, outward velocity, maximum inward curvature, damping ora combination thereof.

In all embodiments the scanning step may comprise delivering to theocular tissue, via the laser source, radiation with a wavelength fromabout 1260 nm to about 1370 nm and imaging the ocular tissue.

Also in all embodiments the calculating step may comprise delivering anair-puff with a force sufficient to induce a deformation and applanationin the optical tissue, measuring a pressure of the air-puff at aplurality of time points during deformation and applanation of theocular tissue as a temporal pressure profile and correlating thepressures measured at times of applanation of the ocular tissue with themeasured temporal pressure profile. Further to the calculating step themethod may comprise displaying images of the deformation and applanationof the ocular tissue. Further still the method may comprise calibratingintraocular pressure by integrating an ocular geometry into the imagesand calculations of the deformation and applanation.

In addition in all embodiments the quantifying step may comprisedelivering a focused micro air-pulse to the ocular tissue to induce alow amplitude displacement therein, measuring the low amplitudedisplacement at a point of excitation or at multiple points ofexcitation at different spatial positions to detect an air-pulse inducedelastic wave, and quantifying, as the biomechanical properties, one ormore characteristics of the displacement of the ocular tissue or of theelastic wave or a combination thereof obtained from the profiles andcorrecting the measured biomechanical properties utilizing the geometryof the ocular tissue. Further to this embodiment the quantifying stepmay comprise displaying images of the displacement of the ocular tissue.

In yet another embodiment of the present invention there is provided anapplanation-optical coherence elastography (Appl-OCE) system formeasuring intraocular pressure, an ocular tissue geometry andbiomechanical properties in an eye of a subject, comprising, as operablylinked components, a scanning laser source; a scanner operably linked toa scanner driver configured to scan the eye with radiation deliveredfrom the laser source; an air-puff generator configured to deliver anair-puff of a force sufficient to deform and applanate a cornea of theeye; an air-pulse generator configured to deliver a focused microair-pulse sufficient to generate a local displacement or an elastic wavewithin the eye; and a computer comprising at least a memory, aprocessor, a digitizer, a display, and at least one network connectionand an interface in electronic communication with the system components.Further to this embodiment the Appl-OCE system may comprise a housing.

In both embodiments the laser source may be a scanning laser sourceconfigured to operate at about 1266 nm to about 1366 nm. Also in bothembodiments the air-puff generator may comprise, in combination, arotary solenoid and a plunger. In addition the air-pulse generator maycomprise an air-pulse supply, an electronically controlled pneumaticsolenoid and an air-pulse controller operably-linked to and configuredto produce a focused micro air-pulse from the air-pulse supply.

In all embodiments the computer may be configured to enableprocessor-executable instructions to produce and display images of theeye from displacement data obtained during the scan, the focused microair-pulse, and the air-puff, to measure a temporal pressure profile fromdeformation and applanation data of the cornea from the air-puff, tocalculate an intraocular pressure from the measured displacement dataand measured air-puff temporal pressure profile, to generate a temporalprofile of a displacement in the ocular tissue induced by the focusedmicro air-pulse, to generate spatio-temporal profiles of an elastic waveproduced within the ocular tissue in response to the air-pulse induceddisplacement thereof, and to quantify one or more characteristics of theair-pulse induced displacement or elastic wave as one or morebiomechanical properties.

In yet another embodiment of the present invention there is provided amethod for determining the health of an eye in a subject, comprising thesteps of scanning the eye of the subject with the scanning laser sourceand the scanner of the applanation-optical coherence elastography(Appl-OCE) system as described supra; delivering to the eye the air-puffand the focused micro air-pulse; displaying images of the eye processedduring the scanning or delivering steps or combination thereof;measuring an intraocular pressure of the eye from data obtained afterdelivering the air-puff; measuring one or more biomechanical propertiesfrom data obtained after delivering the focused micro air-pulse to theeye; and analyzing the intraocular pressure, ocular tissue geometry andone or more biomechanical properties for pathophysiologicalabnormalities, thereby determining the health of the eye.

In this embodiment the step of measuring an intraocular pressure maycomprise measuring a pressure of the air-puff at a plurality of timepoints during deformation and applanation of the cornea and correlatingthe pressures measured at times of applanation of the cornea with ameasured pressure profile thereof. Further to this measuring step themethod may comprise calibrating intraocular pressure by integrating anocular geometry into images and calculations of the deformation andapplanation after delivery of the air-puff and calculating ocular tissuebiomechanical properties utilizing ocular tissue geometry after deliveryof the focused micro air-pulse.

Also in this embodiment the step of measuring one or more biomechanicalproperties step may comprise calculating at a plurality of time points atemporal profile of the displacement in the eye after delivery of theair-pulse; calculating at a plurality of time points spatio-temporalprofiles of an elastic wave generated within the eye in response to thedisplacement thereof, or a combination thereof, and quantifying, as thebiomechanical properties, one or more characteristics of thedisplacement of the eye or of the elastic wave or a combination thereofobtained from the profiles.

In addition in this embodiment the biomechanical properties may compriseaxial displacement, relaxation rate, relaxation process, frequency ofrelaxation process, natural frequency, spectral properties, Young'smodulus, shear modulus, elasticity, viscosity, shear viscosity, maximumdeformation, corneal thickness, corneal curvature, inward velocity,outward velocity, maximum inward curvature, damping or a combinationthereof.

Provided herein are optical imaging systems configured to measure, inocular tissue, the intraocular pressure, to quantify biomechanicalproperties of the ocular tissue and to measure ocular geometry, such asof the cornea, using a single instrument or device. Particularly, thesingle instrument imaging system is an ultrafast applanation opticalcoherence elastography (Appl-OCE) system that comprises aphase-sensitive swept source optical coherence tomography (Phs-SS-OCT)subsystem that provides high-resolution and depth-resolved images of thetarget ocular tissue and an applanation tonometer subsystem configuredto visualize corneal dynamics during noncontact applanation tonometryand to directly measure a focused micro air-pulse induced displacementor a focused micro air-pulse induced elastic wave propagation asdescribed herein. Representative examples of an ocular tissue are, theeye, eye-globe and/or cornea of a subject, an ex vivo eye-globe, an exvivo corneal sample, or any optical tissue mimic.

Applanation Optical Coherence Elastography (Appl-OCE) System

The Applanation Optical Coherence Elastography (Appl-OCE) system 100comprises, as operably linked components a Phase-Sensitive Swept SourceOptical Coherence Tomography (PhS-SSOCT) subsystem for optical coherenceelastography (OCE) and an applanation tonometer subsystem (FIG. 1 )Generally, the PhS-SSOCT subsystem includes, but is not limited to, anoptical coherence tomography device with an elastographic functionalextension or optical coherence elastography (OCE) functionality, anair-puff delivering device, an air-pulse, such as a focused microair-pulse, delivering device, and a computer. Alternatively, the microfocused air-pulse delivering device may be part of the elastographicfunctional extension. The applanation tonometer subsystem generallyincludes, but is not limited to, means for generating a large forceair-puff, a pressure transducer and software to calculate and transmitdata received from delivery of the large force air-puff.

The optical coherence tomography device comprises, in an operably-linkedrelationship, a Fourier Domain Mode Locked (FDML) scanning laser source105 operating to scan a laser beam at white light, near-infrared orinfrared wavelengths, for example, at about 1260 to about 1370 nm,preferably about 1266 nm to about 1366 nm or more preferably about 1316nm, a reference mirror 110, a polarization controller 115, a balancedphotodetector 120, a Bayonet Neill-Concelman (BNC) board 125, a resonantscanner 130 configured to scan the sample 135, such as an ocular tissue,the eye and/or cornea of a subject, an ex vivo eye-globe, an ex vivocorneal sample, or any optical tissue mimic, a resonant scanner driver140 operably linked to the laser source and to the resonant scanner, anda recalibration mirror 145. The scanner driver is operator-configurablefor scanning distance and phase when moving the resonant scanner.

An air-puff generator, configured to generate a air puff for imaging ofthe optical tissue, comprises a solenoid and plunger combination 150connected to the amplifier and configured to fluidly deliver the airpuff. The air-puff is delivered at 155. The air-pulse generatorcomprises an air-pulse supply 160 and an electronically controlledpneumatic solenoid 165 in electronic connection with an air pulsecontroller 170. The air-pulse is delivered at 175.

The applanation tonometer subsystem comprises an air pump 180 configuredto generate a large force air-puff delivered to the sample at 185. Apressure transducer 190 receives data comprising the inward and outwarddeformations and the two points of applanation of the sample and via IOPsoftware 195 calculates the pressure profile.

A housing (not shown) contains all the components of the subsystem. Anelectronic interface 200 connects to a computer 210. The computer isconfigured for controlling the system, data and image processingincluding a digitizer 212 for analog-to-digital and digital-to-analogconverters, and image display 214.

Also provided are ultra-fast methods for quantifying or measuringintraocular pressure and/or performing quantitative elastographicevaluation of the cornea using the noncontact Appl-OCE system.Generally, a large force air-puff is delivered to deform and applanatethe cornea and optical coherence tomography images are taken. Theair-puff induces a deformation in the ocular tissue, causing it todeform inwards. The entire dynamic deformation is imaged withmicrometer-scale spatial resolution and microsecond-scale temporalresolution and integrates ocular geometry into the calculations forcalibration of the intraocular pressure. On the inwards and outwardsprocesses, there is a point at which the cornea is flat or applanated.By measuring the temporal pressure profile of the air-puff, theapplanation times are correlated with an air puff pressure. Theintraocular pressure can then be estimated under the simple assumptionthat the forces on the anterior surface of the cornea (i.e., air-puff)and posterior surface of the cornea (i.e., IOP) are equal when thecornea is applanated (i.e., flat).

To measure the elasticity or stiffness of the cornea with the Appl-OCEsystem, a focused micro air-pulse induces a low amplitude displacement(micro to nanometer-scale) in the cornea that then propagates as anelastic wave. The phase-resolved measurements provide thespatio-temporal profiles of the elastic wave or temporal profile of theair-pulse induced displacement. These two parameters enable furtherquantification of the wave and displacement characteristics, forexample, but not limited to, group velocity, phase velocity, dispersion,relaxation rate, and/or natural frequency, and subsequent ocular tissuestiffness, elasticity, shear modulus, viscosity, or shear viscosity orcombinations thereof. Spectral analysis of the elastic wave andmodel-based viscoelasticity reconstruction then provides adepth-resolved elasticity characterization.

Thus, the present invention further provides a method for clinicallyevaluating the health of an eye and its tissues. The Appl-OCE system isuseful to measure the biomechanical properties of the cornea in itsnatural resting state in the eye-globe with small displacements thatminimize the effects of the corneal nonlinear biomechanical properties.Measuring the IOP and quantifying tissue material properties which aremarkers for ocular tissue health and integrity together enables one toascertain whether abnormal measurements of either are due to apathological IOP or other pathophysiological condition or to inherenttissue biomechanical properties. Particularly, the biomechanicalproperties are one or more of axial displacement, relaxation rate,relaxation process, frequency of the relaxation process, naturalfrequency, spectral properties, Young's modulus, shear modulus,elasticity, viscosity, shear viscosity, maximum deformation, cornealthickness, corneal curvature, inward velocity, outward velocity, maximuminward curvature, and damping.

The following examples are given for the purpose of illustrating variousembodiments of the invention and are not meant to limit the presentinvention in any fashion.

Example 1

Materials and Methods

Agar Phantom Samples

Tissue-mimicking agar phantoms (Difco nutrient agar, Beckton, Dickinsonand Company, Sparks, Md., USA) were used. Concentrations (w/w) of agarare 1%, 1.5% and 2%, n=3 of each concentration.

Porcine Eyes

Fresh porcine eyes (Sioux-Preme Packing Company, Sioux City, Iowa; n=3)are used. Extraneous tissues such as muscles are removed from theeye-globes and all measurements were taken within 24 h of enucleation.The whole eye-globes were placed in a home-built holder for artificialIOP control (17). During testing, the eye-globes are cannulated with two23 G needles for an artificial IOP control. One needle was connected viatubing to a pressure transducer and the other needle was connected viatubing to a microinfusion pump.

Video

Video of noncontact applanation (Video 1) or elastic wave propagation(Video 2) was imaged at a frame rate of ˜7.3 kHz.

Video 1, MP4, 6.5 MB, dx.doi.org/10.1117/1.JBO.22.2.020502.1; and

Video 2, MP4, 4 MB, dx.doi.org/10.1117/1.JBO.22.2.020502.2.

Example 2

Optical Imaging System

Phase-Sensitive Swept-Source Optical Coherence Tomography (PhS-SSOCT)Imaging Subsystem

The phase-sensitive swept source Optical Coherence Tomography system(PhS-SSOCT) (see FIG. 1 ) imaging system utilizes a 4× buffered Fourierdomain model locked (FDML) swept source laser with an A-scan or sweeprate of ˜1.5 MHz, a central wavelength of ˜1316 nm, a scan range of ˜100nm, an axial resolution of ˜16 μm, a phase stability of ˜14 nm, and aresonant scanner at ˜7.3 kHz. The PhS-SSOCT optical imaging system isutilized to image the dynamic spatio-temporal deformation of the corneain response to the air-puff and detect the nano to micrometer-scaledisplacements induced by the focused air-pulse. The PhS-SSOCT imagingsystem is controlled by a computer comprising at least a processor,memory, analog-to-digital (ADC) and digital-to-analog (DAC) converters,a display, and other requisite software and hardware to operate thesystem and at least one network connection.

Applanation Optical Coherence Elastography (Appl-OCE) System

The Applanation Optical Coherence Elastography imaging system (FIG. 1 )comprises the PhS-SSOCT system and means for making intraocular pressuremeasurements, imaging the ocular tissue geometry, and measuring theair-pulse induced displacements, either at the excitation position ordifferent spatial positions to detect the air-pulse induced elastic wavepropagation. The Appl-OCE system utilizes the rotary solenoid andplunger to provide the large force air-puff during the applanationmeasurements. The Appl-OCE system utilizes a focused micro air-pulseexcitation system (18) for the elastographic measurements.

Example 3

PhS-SSOCT Assessment of Elasticity of Optical Samples

Agar Phantom

The propagation of the air-pulse induced elastic wave in atissue-mimicking agar phantom is illustrated in FIG. 2 . The temporalvertical displacement profiles at the indicated distances are plotted.The distances are at about 0.5 mm, 1.0 mm, 1.5 mm, 2.0 mm and 2.5 mmaway from the air-pulse excitation. The largest displacement at all thedistance appears at the time of about 3 ms, and the displacement isfully recovered after about 6 ms for all the excitation distances. Thewave propagation, attenuation, and dispersion can be observed from theshape of the profiles at the various distances and can be also be usedto calculate biomechanical properties.

In order to validate the optical coherence elastography technique, thestiffness of agar phantoms of various concentrations (1%, 1.5%, and 2%w/w, n=3 of each concertation) assessed by optical coherenceelastography and measured by the “gold standard” uniaxial mechanicalcompression testing are compared. The Young's modulus as obtained byboth methods of the phantoms is plotted in FIG. 3 . The results showthat the optical coherence elastography and uniaxial mechanicalcompression test generates comparable results at all three agarconcentrations. Especially, at the agar concentration of 1%, the resultsfrom optical coherence elastography are very similar as the uniaxialmechanical compression test.

Example 4

Appl-OCE Intraocular Pressure, Corneal Geometry and BiomechanicalMeasurements on an Ex Vivo Cornea

The dynamic tissue responses to air-puff and micro air-pulse excitationsare detected with the Appl-OCE system. During applanation, a large forceair-puff was directed at the central region of the porcine cornea insitu in the whole eye-globe configuration, which was recorded by the OCTsystem with a frame rate of ˜7.3 kHz as Video 1 (1000× slower thanreal-time) (FIG. 4 ). The total duration is approximately 25 ms. Duringthe inward and outward deformations, there are two times when the corneais applanated at 1.4 and 15.3 ms after excitation, respectively.

To calculate the intraocular pressure (IOP), it was assumed that theforce on the anterior surface, i.e. the air-puff, and posterior surface,i.e. the IOP, of the cornea were equal at the times when the cornea wasapplanated. The time between applanation states were used to obtain theintraocular pressure from the air-puff pressure profile, which wasmeasured by a pressure transducer. Measuring the intraocular pressurecan also be accomplished by proper synchronization rather than thedifference between the applanation times. The air-puff pressure profilecan be adjusted to a suitable dynamic range for the target with orwithout a priori information. The dynamic range of pressure displayed inthis document is not truly indicative of the detectable pressure range.Four applanation measurements were taken for each porcine sample at eachIOP setting. To corroborate the results, IOP measurements were also madewith a rebound tonometer (TonoVet, iCareUSA, North Carolina) immediatelyafter the respective applanation measurements by the Appl-OCE system.Five measurements were made for each sample at each IOP by the reboundtonometer.

After the applanation measurements, a focused micro air-pulse induced anelastic wave in the cornea, which was also detected by the samephase-sensitive OCT system as in FIG. 1 . Briefly, the air-pulse induceda localized displacement, when then propagated transversely as anelastic wave, which was imaged by repeated B-scans. The number ofA-scans in each B-scan was a multiple of four to ensure that eachrepeated A-scan at a given spatial position was from the same bufferedsweep since the FDML laser utilized 4× buffering (21). The phase datawas corrected to remove surface motion and refractive index mismatchartifacts, with the refractive index of the cornea as 1.376 (22, 23).Selected temporal frames from Video 2 (1000× slower than real-time) ofthe air-pulse induced elastic wave propagating across the porcine corneaat 10 mmHg IOP (FIG. 5 ). The dark regions near the apex are due tophase unwrapping errors, and these positions were not used forelasticity quantification. The elastic wave velocity was calculated bycross-correlation analysis and linear fitting of the temporaldisplacement profiles at different spatial positions in the linear scanregion. Similar to the applanation measurements, four line measurementsover the same apical region were taken for each sample for each IOPsetting. The OCE measurements were taken along the nasal/temporal axisof each cornea to limit the effects of corneal mechanical anisotropy onthe OCE measurements (24). The Young's modulus was estimated from thegroup velocity using the surface wave equation as described (16, 25).

The intraocular pressure as measured by Appl-OCE (horizontal stripes)and rebound tonometry (vertical stripes) along with the stiffness of thecornea (right bar) estimated by OCE is shown (FIG. 6 ). The IOP set bythe IOP control system is also plotted for easy comparison. The data arepresented as the mean±standard deviation of all measurements from allthree samples for a given controlled IOP. Statistical testing byStudent's t-test was performed to determine if the measured andcontrolled IOPs were similar. The results showed that the IOP measuredby OCT applanation was not significantly different from the IOP set bythe controller, albeit only marginally (P=0.07). However, the IOP, asmeasured by the rebound tonometer, was significantly different from theIOP as set by the IOP controller (P<0.001). The inter-samplemean±standard deviation of the IOP measurements by both techniques,corneal stiffness, and CCT are presented in Table 1. IOP is measured bya rebound tonometer and Appl-OCE applanation, corneal stiffness ismeasured by optical corneal elasticity, and CCT was calculated from theOCT structural image, assuming that the cornea had a constant refractiveindex of 1.376 (23).

TABLE 1 Rebound Young's IOP Tonometry Appl-OCE Modulus CCT controller(mm Hg) (mm HG) (kPa) (μm) 10  5.8 ± 2.5  7.8 ± 2.4 14.5 ± 2.3 1058 ±97  15 11.1 ± 2.2 13.5 ± 0.2 50.0 ± 2.0 985 ± 86 20 17.7 ± 2.0 21.3 ±2.0   158 ± 31.8 983 ± 74

These results show good correlation with the IOP as set by theartificial IOP control system. Generally, IOP measurements performed byair-puff applanation tend to overestimate IOP (26), however, the OCTapplanation results obtained herein slightly underestimated IOP, exceptat 20 mm Hg, where the IOP was overestimated by 11 mm Hg. The reboundtonometer is known to underestimate IOP (27) which was corroboratedherein.

The following references are cited herein.

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The present invention is well adapted to attain the ends and advantagesmentioned as well as those that are inherent therein. The particularembodiments disclosed above are illustrative only, as the presentinvention may be modified and practiced in different but equivalentmanners apparent to those skilled in the field having the benefit of theteachings herein. Furthermore, no limitations are intended to thedetails of construction or design herein shown, other than as describedin the claims below. It is therefore evident that the particularillustrative embodiments disclosed above may be altered or modified andall such variations are considered within the scope and spirit of thepresent invention.

What is claimed is:
 1. A system for measuring intraocular pressure,ocular tissue geometry and biomechanical properties of an ocular tissue,comprising: in one instrument, an optical coherence tomographysubsystem, wherein the optical coherence tomography subsystem comprises:means for scanning the ocular tissue, means for delivering an air-puffto the ocular tissue, and means for delivering a focused micro air-pulseto the ocular tissue; and an applanation tonometer subsystem inelectronic communication with the optical coherence tomographysubsystem.
 2. The system of claim 1, further comprising: a housingcontaining the subsystems; a computer comprising at least a memory, aprocessor, a digitizer, a display, and at least one network connection;and an interface in electronic communication with said subsystems andwith the computer.
 3. The system of claim 2, wherein the computer isconfigured to control the subsystems, to process data received from thesubsystems, to generate one or more images from processed data, and todisplay said one or more images.
 4. The system of claim 1, wherein themeans for scanning the ocular tissue comprises, in electroniccommunication: a scanning laser source configured to operate at about1260 nm to about 1370 nm; across the ocular tissue; and a scanner driverconfigured to move the resonant scanner over the ocular tissue withoperator-configurable scanning distance and phase.
 5. The system ofclaim 1, wherein the means for delivering the air-puff to the oculartissue comprises, in combination, a rotary solenoid and a plungerconfigured to deliver the air-puff with a force sufficient to deform theocular tissue.
 6. The system of claim 1, wherein the means fordelivering the focused micro air-pulse to the ocular tissue comprises,in electronic communication: an air-pulse supply; an electronicallycontrolled pneumatic solenoid; and an air-pulse controller configured toproduce the focused micro air-pulse from the air-pulse supply.
 7. Thesystem of claim 1, wherein the applanation tonometer subsystemcomprises: means for delivering an air-puff to the ocular tissue; meansfor measuring a temporal pressure profile from deformation andapplanation of the ocular tissue from the air-puff delivered thereto;and means for calculating an intraocular pressure from the temporalpressure profile and imaged ocular tissue deformation and applanation.8. The system of claim 7, wherein the means for measuring the temporalpressure profile of the ocular tissue is a pressure transducerconfigured to measure an air-puff pressure at a plurality of time pointsduring deformation and applanation of the ocular tissue.
 9. The systemof claim 7, wherein the means for calculating the intraocular pressurecomprises software configured to correlate the times of applanation ofthe ocular tissue with a temporal pressure profile and to applycorrections as needed.
 10. The system of claim 1, wherein the oculartissue comprises an in vivo or an ex vivo eye-globe, an in vivo or an exvivo corneal tissue or an ocular tissue mimic.
 11. A method formeasuring intraocular pressure, ocular tissue geometry and biomechanicalproperties of an ocular tissue in one instrument, comprising: scanningthe ocular tissue of an eye globe with a laser source in the opticalcoherence tomography subsystem of claim 1; obtaining optical coherencetomography images; calculating the intraocular pressure of the eye globevia the applanation tonometer subsystem; measuring the geometry of theocular tissue based on the optical coherence tomography images; andquantifying the biomechanical properties of the ocular tissue via theoptical coherence tomography subsystem.
 12. The method of claim 11,further comprising: displaying one or more images obtained during thescanning step.
 13. The method of claim 11, further comprising:identifying one or more abnormalities in the ocular tissue based on thecalculated intraocular pressure, an imaged ocular tissue geometry andthe measured biomechanical properties.
 14. The method of claim 11,wherein the scanning step comprises: delivering to the ocular tissue,via the laser source, radiation with a wavelength from about 1260 nm toabout 1370 nm; and imaging the ocular tissue.
 15. The method of claim11, wherein the calculating step comprises: delivering an air-puff tothe ocular tissue with a force sufficient to induce a deformation andapplanation in the optical tissue; measuring a pressure of the air-puffat a plurality of time points during deformation and applanation of theocular tissue as a temporal pressure profile; and correlating thepressures measured at times of applanation of the ocular tissue with themeasured temporal pressure profile.
 16. The method of claim 15, furthercomprising: displaying images of the deformation and applanation of theocular tissue.
 17. The method of claim 16, further comprising:calibrating intraocular pressure by integrating an ocular geometry intothe images and calculations of the deformation and applanation.
 18. Themethod of claim 11, wherein the quantifying step comprises: delivering afocused micro air-pulse to the ocular tissue to induce a low amplitudedisplacement therein; measuring the low amplitude displacement at apoint of excitation or at multiple points of excitation at differentspatial positions to detect an air-pulse induced elastic wave; andquantifying, as the biomechanical properties, one or morecharacteristics of the displacement of the ocular tissue or of theelastic wave or a combination thereof obtained from the profiles; andcorrecting the measured biomechanical properties utilizing the geometryof the ocular tissue.
 19. The method of claim 18, further comprising:displaying images of the displacement of the ocular tissue.
 20. Themethod of claim 11, wherein the biomechanical properties comprise axialdisplacement, relaxation rate, relaxation process, frequency ofrelaxation process, natural frequency, spectral properties, Young'smodulus, elasticity, viscosity, maximum deformation, corneal thickness,corneal curvature, inward velocity, outward velocity, maximum inwardcurvature, damping or a combination thereof.
 21. An applanation-opticalcoherence elastography (Appl-OCE) system for measuring intraocularpressure, an ocular tissue geometry and biomechanical properties in aneye of a subject, comprising, as operably linked components: a scanninglaser source; a scanner operably linked to a scanner driver configuredto scan the eye with radiation delivered from the laser source; anair-puff generator configured to deliver an air-puff of a forcesufficient to deform and applanate a cornea of the eye; an air-pulsegenerator configured to deliver a focused micro air-pulse sufficient togenerate a localized displacement or an elastic wave within the eye; anda computer comprising at least a memory, a processor, a digitizer, adisplay, and at least one network connection and an interface inelectronic communication with the system components.
 22. The Appl-OCEsystem of claim 21, further comprising a housing.
 23. The Appl-OCEsystem of claim 21, wherein the laser source is a scanning laser sourceconfigured to operate at about 1266 nm to about 1366 nm.
 24. TheAppl-OCE system of claim 21, wherein the air-puff generator comprises incombination, a rotary solenoid and a plunger.
 25. The Appl-OCE system ofclaim 21, wherein the air-pulse generator comprises: an air-pulsesupply; an electronically controlled pneumatic solenoid; and anair-pulse controller operably-linked to and configured to produce afocused micro air-pulse from the air-pulse supply.
 26. The Appl-OCEsystem of claim 21, wherein the computer is configured to enableprocessor-executable instructions to: produce and display images of theeye from displacement data obtained during the scan, the focused microair-pulse and the air-puff; measure a temporal pressure profile fromdeformation and applanation data of the cornea from the air-puff;calculate an intraocular pressure from the measured displacement dataand measured air-puff temporal pressure profile; generate a temporalprofile of a displacement in the ocular tissue induced by the focusedmicro air-pulse; generate spatio-temporal profiles of an elastic waveproduced within the ocular tissue in response to the air-pulse induceddisplacement thereof; and quantify one or more characteristics of theair-pulse induced displacement or elastic wave as one or morebiomechanical properties.
 27. A method for determining the health of aneye in a subject, comprising the steps of: scanning the eye of thesubject with the scanning laser source and scanner of theapplanation-optical coherence elastography (Appl-OCE) system of claim21; delivering to the eye the air-puff and the focused micro air-pulse;displaying images of the eye processed during the scanning or deliveringsteps or combination thereof; measuring an intraocular pressure of theeye from data obtained after delivering the air-puff; measuring one ormore biomechanical properties from data obtained after delivering thefocused micro air-pulse to the eye; and analyzing the intraocularpressure, ocular tissue geometry and one or more biomechanicalproperties for pathophysiological abnormalities, thereby determining thehealth of the eye.
 28. The method of claim 27, wherein the step ofmeasuring an intraocular pressure comprises: measuring a pressure of theair-puff at a plurality of time points during deformation andapplanation of the cornea; and correlating the pressures measured attimes of applanation of the cornea with a measured pressure profilethereof.
 29. The method of claim 28, further comprising: calibratingintraocular pressure by integrating an ocular geometry into images andcalculations of the deformation and applanation after delivery of theair-puff; and calculating ocular tissue biomechanical propertiesutilizing ocular tissue geometry after delivery of the focused microair-pulse.
 30. The method of claim 27, wherein the step of measuring oneor more biomechanical properties step comprises: calculating at aplurality of time points a temporal profile of the displacement in theeye after delivery of the air-pulse; calculating at a plurality of timepoints spatio-temporal profiles of an elastic wave generated within theeye in response to the displacement thereof; or a combination thereof;and quantifying, as the biomechanical properties, one or morecharacteristics of the displacement of the eye or of the elastic wave ora combination thereof obtained from the profiles.
 31. The method ofclaim 27, wherein the biomechanical properties comprise axialdisplacement, relaxation rate, relaxation process, frequency ofrelaxation process, natural frequency, spectral properties, Young'smodulus, shear modulus, elasticity, viscosity, shear viscosity, maximumdeformation, corneal thickness, corneal curvature, inward velocity,outward velocity, maximum inward curvature, damping or a combinationthereof.